Current standards of care for cartilage injuries cannot reliably provide sustained clinical improvement, so there is much interest in the development of alternative, biological approaches towards repair/regeneration. Regenerative medicine approaches typically involve the recruitment or transplantation of endogenous mesenchymal progenitor cells (MFCs) to the defect site. Under controlled conditions, these cells have the potential to proliferate, differentiate along the relevant musculoskeletal lineage and regenerate damaged tissue matrix. However, the intra-articular environment can be hostile to chondrogenesis; specifically, inflammation within the injured joint can inhibit tissue regeneration. Joint inflammation is mediated locally by cytokines such as interleukin-1 and tumor necrosis factor-a. Although proinflammatory cytokines play an important role in the pathogenesis of osteoarthritis, little is known about how they affect cartilage repair strategies involving MFCs. The central hypothesis shaping this project is that inflammation secondary to joint trauma or subsequent surgical intervention can inhibit the regenerative activity of MFCs within the cartilage defect, thus limiting repair. During the mentored phase, a toolset of reporter constructs were developed for monitoring the state of human MFC differentiation, using these constructs to non-invasively track inflammatory and chondrogenic activity within an immunocompromised rat model of cartilage injury. Upon transition to the independent phase of the project, tools developed during the mentored phase will help characterize the proinflammatory environment resulting from surgically-induced joint trauma, identifying factors that impair chondrogenesis and defect repair. Both immunologically-competent and -incompetent animal models of joint injury will be used to determine the ability of MFCs to repair/regenerate cartilage when protected from the identified factors. At the end of this project period, we will have a better understanding of how the joint environment - particularly inflammatory signaling - impacts the ultimate success of cartilage regeneration strategies using heterogeneous progenitor cell populations.